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Fumitaka Kikkawa

Publications and source records attributed to Fumitaka Kikkawa.

At least 55 records · Page 3Linked to original sources
PubMed2004

Expression of placental leucine aminopeptidase is associated with a poor outcome in endometrial endometrioid adenocarcinoma.

OBJECTIVE: Placental leucine aminopeptidase (P-LAP) is a cell surface aminopeptidase (oxytocinase). We cloned P-LAP cDNA and found a widespread tissue distribution of P-LAP. Since P-LAP can degrade several small peptide hormones such as oxytocin, this enzyme may affect many cellular functions of carcinoma cells as well as normal cells. This study investigated whether the expression of P-LAP correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma. METHODS: Histologic sections of formalin-fixed, paraffin-embedded specimens from 99 primary endometrial carcinomas were stained for P-LAP using polyclonal P-LAP antibody. Disease-free survival and other clinicopathologic characteristics were analyzed according to the intensity of P-LAP staining. RESULTS: Of 99 cases, 69 (69.7%) showed specific P-LAP immunostaining. We found a positive correlation between the expression of P-LAP and histological grade (p < 0.01), surgical stage of the disease (p = 0.02), myometrial invasion (p = 0.01), lymph node involvement (p < 0.01), and vascular infiltration (p < 0.01). In patients who had strongly positive P-LAP staining, the disease-free interval was significantly lower than in patients who had negative or weakly positive P-LAP staining (p < 0.01). Multivariate analysis demonstrated that strongly immunoreactive P-LAP (odds ratio, 12.8; 95% confidence interval, 2.84-58.8; p < 0.01) and surgical stage (odds ratio, 8.78; 95% confidence interval, 2.77-27.8; p < 0.01) are independent prognostic factors. CONCLUSIONS: This study suggests P-LAP as an independent prognosticator of clinical outcome in patients with endometrial carcinoma. Therefore, assessment of the P-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma.

Analysis of Variance↗
PubMed2004

Regulatory role of membrane-bound peptidases in the progression of gynecologic malignancies.

Membrane-bound peptidases play a key role in the control of growth, differentiation, and signal transduction of many cellular systems by degrading bioactive peptides. Thus, abnormal changes in their expression pattern and catalytic function result in altered peptide activation, which contributes to neoplastic transformation or progression. In this review, we describe our recent findings along with work from other groups on the expression and biological functions of membrane-bound peptidases in cancer, focusing on the regulatory roles of three peptidases, aminopeptidase A (APA), neutral endopeptidase (NEP) and placental leucine aminopeptidase (P-LAP), in the progression of gynecologic malignancies. APA, NEP and P-LAP are differentially expressed and localized in various gynecologic malignancies including cervical cancer, endometrial cancer, ovarian cancer and choriocarcinoma in a tumor-type specific pattern. The expression levels are up- or down-regulated depending on histological grade or disease progression. These peptidases play regulatory roles in tumor cell proliferation, invasion or angiogenesis via degradation/inactivation of target peptides such as angiotensin II, endothelin-1 and oxytocin, which act on cancer cells as stimulatory or inhibitory factors. Thus, membrane-bound peptidases may become not only a new diagnostic/prognostic marker, but also a novel molecular target for the treatment of gynecologic malignancies.

Disease Progression↗
PubMed2003

Adipocyte-derived leucine aminopeptidase suppresses angiogenesis in human endometrial carcinoma via renin-angiotensin system.

PURPOSE: Angiotensin (Ang) II was reported to induce vascular endothelial growth factor (VEGF) expression in various cells. Adipocyte-derived leucine aminopeptidase (A-LAP) is a novel member of the M1 family of zinc metallopeptidases. Enzymatic characterization demonstrated that A-LAP hydrolyzes Ang II. This study examined the role of A-LAP in angiogenesis of human endometrial carcinoma. EXPERIMENTAL DESIGN: We investigated whether Ang II induces VEGF expression in human endometrial carcinoma cells. To investigate the possible function of A-LAP in angiogenesis of endometrial carcinoma, we transfected A-LAP cDNA into HEC-1A cells, showing the lowest expression of A-LAP. RESULTS: In the present study, we showed that Ang II enhanced VEGF expression in a dose-dependent manner in endometrial carcinoma cells (HEC-1A cells). Overexpression of A-LAP attenuated Ang II-induced VEGF expression in HEC-1A cells. In addition, Human umbilical vascular endothelial cell migration was increased in conditioned media from Ang II-treated wild-type cells, but not in conditioned media from Ang II-treated A-LAP-overexpressing cells (HEC-1A-A-LAP cells). In an in vivo study, we showed that A-LAP overexpression in endometrial carcinoma cells results in a reduction of VEGF immunoreactivity and the number of blood vessels within tumors. CONCLUSIONS: Our study demonstrates that it is feasible to overexpress Ang II-degrading enzymes in cultured cells and that this overexpression attenuated some effects of exogenous and endogenous Ang II. These experiments are a first step toward the development of novel strategies to selectively antagonize locally generated Ang II and suppress VEGF-induced angiogenesis in endometrial carcinoma.

Adipocytes↗
PubMed2003

Usefulness of preoperative chemoradiation in locally advanced cervical carcinoma.

This study investigated response rate, toxicity, and influence on intra- and postoperative complications of neoadjuvant concurrent chemoradiation in locally advanced (Figo IB2-IIIB) cervical carcinomas. Twenty-eight patients (median age 46.5 years, age range 29-73 years), diagnosed as having squamous cell carcinomas (n=21), adenocarcinomas (n=6), and undifferentiated carcinoma (n=1), entered this study. The chemoradiation protocol included external radiotherapy to the pelvis (39.6 Gy), intra-arterial or intravenous infusion of cisplatin (70 mg/m2 on days 1 and 22), and 24-hour continuous intravenous infusion of 5-fluorouracil (700 mg/m2 on days 1-4 and 22-25). Two weeks after the end of chemoradiotherapy, the patients underwent restaging followed by suitable operation including pelvic lymphadenectomy. The median follow-up period in the surviving patients was 13.1 months. The response rate for chemoradiation was 93% (26/28). The 2-year disease free survival was 85.2%. Grade 3-4 neutropenia was observed in 14 patients (50%), 4 patients (14%) showed grade 3 anemia, and 5 patients (17.8%) showed grade 3-4 thrombocytopenia. Nineteen patients (67.8%) could undergo surgery after concurrent chemoradiation. Pathological examination revealed a complete response (pT0) in 7 patients, and 5 patients showed only microscopic residual disease (pTmic). In 4 patients, there were intraoperative complications: vesical lesions in 2 (10%) and small intestine lesions in 2 (10%). Neoadjuvant therapy with concurrent chemoradiation for locally advanced cervical carcinoma is effective, safe, and useful for increasing operability rates as well as decreasing intra- and postoperative complications. Therefore, neoadjuvant concurrent chemoradiation should be considered for treatment in patients with locally advanced cervical carcinomas who could not undergo primary operation.

Adenocarcinoma↗
PubMed2003

Placental leucine aminopeptidase/oxytocinase gene regulation by activator protein-2 in BeWo cell model of human trophoblast differentiation.

Placental leucine aminopeptidase (P-LAP) is located preferentially in syncytiotrophoblasts in human placenta. Here we investigated P-LAP expression and the regulatory mechanisms in BeWo choriocarcinoma cells with forskolin (FSK)-induced differentiation. Morphologically differentiated cells revealed enhanced P-LAP staining. FSK significantly increased P-LAP activity and mRNA. Deletion or mutation of activator protein-2 (AP-2) binding site in the footprint-3 (-216 to -172) of P-LAP promoter abrogated the stimulatory effects of FSK on luciferase activity of the construct -216/+49. In AP-2-deficient Hep-G2 cells, FSK failed to stimulate luciferase activity of the construct -216/+49. Among the isoforms, BeWo expressed AP-2alpha and AP-2gamma, while FSK increased only AP-2alpha. These results suggest differentiation-dependent P-LAP expression in trophoblasts, which involves increased AP-2alpha binding.

Base Sequence↗
PubMed2003

Increased adhesion potency of ovarian carcinoma cells to mesothelial cells by overexpression of dipeptidyl peptidase IV.

Dipeptidyl peptidase IV (DPPIV), cell surface peptidase, works as an adhesion molecule as well as an enzyme. To investigate the role of DPPIV as an adhesion molecule of ovarian carcinoma cells to mesothelial cells, ovarian carcinoma (SKOV3 and NOS4) cells were transfected with a sense and an antisense cDNA coding human DPPIV. The adhesion potency of these transfected cells to fibronectin- and collagen-coated plates and mesothelial cells were examined with or without fibronectin. Flow cytometry and immunohistochemistry demonstrated DPPIV in ovarian carcinoma cells. The adhesion rate of DPPIV-transfected SKOV3 (SKDPIV) cells to fibronectin-coated plates was significantly higher than SKOV3 cells, while there was no difference in the adhesion rate to non-coated plates between SKDPIV and SKOV3 cells. The adhesion rates of vector-transfected SKOV3 (SKpcDNA) cells to coating and noncoating plates were similar to those of SKOV3 cells. SKDPIV cells showed twofold adhesion potency to mesothelial cells compared to SKOV3 cells. Furthermore, an addition of soluble fibronectin resulted in a dose-dependent increase in the adhesion rate of SKDPPIV cells, but not in either SKOV3 or SKpcDNA cells. Antisense-transfected NOS4 cells decreased the adhesion potency compared to NOS4 and vector-transfected NOS4 cells. In conclusion, ovarian carcinoma cells express DPPIV and adhere to human mesothelial cells in part by DPPIV. This adhesion mechanism of DPPIV is mediated by immobilized and soluble fibronectin.

Carcinoma↗
PubMed2003

Dipeptidyl peptidase IV overexpression induces up-regulation of E-cadherin and tissue inhibitors of matrix metalloproteinases, resulting in decreased invasive potential in ovarian carcinoma cells.

Dipeptidyl peptidase IV (DPPIV/CD26) is a multifunctional cell surface aminopeptidase that is widely expressed in different cell types. Our previous study demonstrated a possible link between DPPIV expression and decreased i.p. dissemination and loss of invasive potential of ovarian carcinoma. In this report, we examined the mechanisms of the anti-invasive ability of DPPIV in greater detail. Expression of E-cadherin and beta-catenin was positively correlated with DPPIV expression among five independent ovarian carcinoma cell lines. The introduction of DPPIV cDNA into an ovarian carcinoma cell line (SKOV3) with low DPPIV expression enhanced the expression of E-cadherin and beta-catenin, with a cellular morphological change from a fibroblastic and motile phenotype to an epithelial phenotype. In addition, matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase, important markers associated with invasive and metastatic potential, were remarkably reduced. In contrast, tissue inhibitors of matrix metalloproteinases were up-regulated by DPPIV transfection. Furthermore, suppression of the phosphorylation levels of mitogen-activated protein kinase isoform, extracellular signal-regulated kinase, was observed in DPPIV-overexpressing cells. To our knowledge, this is the first evidence that increasing DPPIV expression may contribute to prolonged survival by up-regulation of E-cadherin and tissue inhibitors of matrix metalloproteinases.

Animals↗
PubMed2003

Cushing's syndrome due to ovarian serous adenocarcinoma secreting multiple endocrine substances: a case report and immunohistochemical analysis.

BACKGROUND: Although Cushing's syndrome arises from various neuroendocrine tumors secreting adrenocorticotropin (ACTH) ectopically, ovarian carcinoma rarely causes this syndrome. CASE: A 66-year-old woman presented with facial swelling and skin pigmentation. She manifested hypercortisolemia, high plasma ACTH, and lack of dexamethasone suppression. MRI showed a solid ovarian tumor and resection of the tumor led to normalization of ACTH and cortisol levels. In addition, elevated serum vasopressin (ADH) and alpha-fetoprotein (AFP) were found, which were also normalized after removal of tumors. Pathological diagnosis was serous adenocarcinoma with neuroendocrine and hepatoid features. Immunohistochemistry detected immunoreactivity of chromogranin A, ACTH, ADH, and AFP in tumor cells. CONCLUSION: This is a very rare case of successful treatment of Cushing's syndrome arising from an ovarian adenocarcinoma secreting multiple endocrine substances.

Adrenocorticotropic Hormone↗
PubMed2003

Oncolytic viral therapy for human ovarian cancer using a novel replication-competent herpes simplex virus type I mutant in a mouse model.

OBJECTIVE: Attenuated mutant strains of herpes simplex virus (HSV) have been effectively used for treatment of malignant brain tumors. As HSV-1 can infect and lyse a variety of cell types, other malignancies may also benefit from such treatment. We sought to test the feasibility of HSV-1 mutant-mediated gene therapy treatment of ovarian cancer. METHODS: We prepared two attenuated mutant HSV-1 strains. An HSV-1 mutant, hrR3, has replaced the gene encoding ribonucleotide reductase (RR) with the lacZ reporter gene. We also developed a new replication-competent HSV-1 mutant, HR522; this virus, expressing the lacZ reporter gene, induces syncytium formation in infected cells. We compared the efficacy of HR522 with, paclitaxel (Taxol) and hrR3 in the treatment of nude mice harboring human ovarian cancer cells. We also examined the effect of the prodrug ganciclovir (GCV) on the treatment mediated by these HSVs. Survival was evaluated by Kaplan-Meier method and log-rank test. RESULTS: The survival of mice treated with a high-titer hrR3 (5 x 10(7) plaque-forming units [PFU]) was significantly prolonged as compared with the group given paclitaxel (P < 0.0001, log-rank test). Although the survival of mice treated with high-titer HR522 (5 x 10(7) PFU) was not significantly prolonged compared with paclitaxel-treated group (P = 0.212, log-rank test), GCV markedly enhanced the efficacy of HR522 administration (P < 0.005, vs paclitaxel, log-rank test). The lacZ gene product, visualized using 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) histochemistry, was detected in HR522-treated tumors in areas also exhibiting apoptotic changes. CONCLUSIONS: These findings indicate that the combination of HR522 and GCV possesses significant therapeutic potential for treatment of ovarian cancer. Such viral therapy offers a novel approach to reductions in the dissemination of ovarian cancer.

Animals↗
PubMed2003

Dipeptidyl peptidase IV expression in endometrial endometrioid adenocarcinoma and its inverse correlation with tumor grade.

OBJECTIVES: Dipeptidyl peptidase IV (DPPIV)/CD26 is a cell surface aminopeptidase. This study investigated the expression and localization of DPPIV in endometrial endometrioid adenocarcinomas of different grades. STUDY DESIGN: Immunohistochemical analysis was performed by using DPPIV and regulated on activation, normal T-cell expressed and secreted (RANTES) specific monoclonal antibodies. Cell proliferation was evaluated by bromodeoxyuridine (BrdU) uptake assay. RESULTS: Immunohistochemical analyses showed that DPPIV was strongly or moderately stained in glandular cells of the normal secretory phase. In endometrial adenocarcinoma, the DPPIV expression decreased with advancing grade (P <.01). Furthermore, RANTES, one of the possible DPPIV substrates, was highly expressed in all grades of endometrial adenocarcinoma cells. The addition of RANTES to endometrial adenocarcinoma cells increased proliferation in a concentration-dependent manner. CONCLUSION: DPPIV is expressed in normal endometrial glandular cells, but its expression in endometrial adenocarcinoma is down-regulated with increasing grade. Our data also suggest a regulatory role of this ectoenzyme in neoplastic transformation and progression of endometrial adenocarcinomas possibly by degrading certain bioactive peptides such as RANTES.

Carcinoma, Endometrioid↗
PubMed2003

Interleukin-1beta stimulates placental leucine aminopeptidase/oxytocinase expression in BeWo choriocarcinoma cells.

In addition to prostaglandins, inflammatory cytokines induce uterine contraction via oxytocin (OT). Placental leucine aminopeptidase (P-LAP), an oxytocinase that is identical to cystine aminopeptidase, destroys OT activity. Patients with spontaneous preterm delivery have higher concentrations of inflammatory cytokines and lower P-LAP activities than those with normal delivery. In addition, the P-LAP promoter region contains putative binding sites for cytokine-induced transcription factors. We therefore postulated that inflammatory cytokines suppress P-LAP expression and examined this notion using BeWo choriocarcinoma cells cultured in the presence of cytokines. However, interleukin-1beta (IL-1beta) increased P-LAP activity in a time- and dose-dependent manner. Furthermore, Western blot analysis showed a dose-dependent increase of P-LAP proteins. We also detected IL-1 type I receptor mRNA in BeWo cells by RT-PCR. Semi-quantitative RT-PCR and Southern blot analysis showed that IL-1beta also increased P-LAP mRNA, which was abrogated by prior exposure to cycloheximide. Luciferase assays did not reveal any regulatory regions that could explain IL-1beta-induced P-LAP mRNA accumulation within 1.1 kb upstream of the P-LAP gene. Immunohistochemical analysis of human placenta with chorioamnionitis demonstrated prominent P-LAP staining at sites of abundant inflammatory cell infiltration. These findings indicated that prolonged exposure to IL-1beta induces P-LAP in the trophoblasts, possibly via other de-novo protein synthesis, which contradicted our initial hypothesis.

Choriocarcinoma↗
PubMed2003

Neutral endopeptidase/CD10 expression in the stroma of epithelial ovarian carcinoma.

This study investigated the immunohistochemical expression and localization of neutral endopeptidase (NEP) (CD10), which plays a functional role by degrading bioactive peptides, in ovarian tumors. In normal ovaries and benign cystadenomas, NEP was not detected in any epithelial or stromal cells. In borderline tumors, NEP was detected in the stromal cells in 6 of 7 serous tumors, but not in those from mucinous tumors. In ovarian carcinomas, NEP in the stromal cells was observed in 13 of 20 serous, 8 of 10 endometrioid, and 7 of 10 clear-cell adenocarcinomas. NEP was weakly detected in only 1 of 9 mucinous adenocarcinomas. The staining intensity of stromal NEP was decreased in grades 2 and 3 serous carcinomas compared with that in grade 1 serous carcinomas. In conclusion, NEP was specifically expressed in the stroma of borderline and malignant ovarian tumors, but not in adenomas. Furthermore, stromal NEP was downregulated as the histological grade advanced. These results suggest that NEP may play a role in the regulation of neoplastic transformation and tumor differentiation in epithelial ovarian carcinomas.

Adenocarcinoma, Clear Cell↗
PubMed2003

Expression of placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in human normal and malignant invasive trophoblastic cells.

We recently identified two novel aminopeptidases, placental leucine aminopeptidase (P-LAP) and adipocyte-derived leucine aminopeptidase (A-LAP). Enzymatically, P-LAP degrades oxytocin, vasopressin, and angiotensin III, while A-LAP degrades angiotensin II and kallidin. In this study we investigated the expression and localization of P-LAP and A-LAP in human trophoblastic cells in the normal placenta (n = 26), gestational choriocarcinoma (n = 8), and placental site trophoblastic tumor (n = 3). On immunoblot analysis both P-LAP and A-LAP proteins were detected in normal placenta and five choriocarcinoma tissues, as well as in two choriocarcinoma cell lines. Immunohistochemical staining of normal placental tissues demonstrated that P-LAP was not only localized in villous syncytiotrophoblasts but also highly expressed in extravillous trophoblasts (EVTs) invading the decidua or maternal spiral arteries. The expression level of P-LAP on these invasive EVTs reached a maximum during the late first to second trimesters of pregnancy, and it decreased in the third trimester. Similarly, A-LAP was strongly expressed in EVTs invading the decidua or spiral arteries in the second trimester of pregnancy, while it was weakly or moderately expressed in villous cytotrophoblasts or EVTs located in the cell columns. These two aminopeptidases were more strongly expressed in all eight choriocarcinomas and three placental site trophoblastic tumors and mainly localized to the intermediate-type trophoblastic tumor cells invading the uterine myometrium or stromal vessels. In summary P-LAP and A-LAP were predominantly expressed in the invasive phenotype of EVTs during placentation, as well as in the invasive tumor cells of trophoblastic neoplasms. These results suggest the involvement of these aminopeptidases in invasiveness of both normal and malignant intermediate-type trophoblasts possibly through degradation of specific peptide substrates.

Adipocytes↗
PubMed2003

Long-term prognosis of stage I ovarian carcinoma. Prognostic importance of intraoperative rupture.

OBJECTIVE: There are a few long-term follow-up studies of patients with stage I ovarian carcinoma. The objective of this study was to evaluate prognostic factors for long-term survival. METHODS: Two hundred fourteen stage I ovarian carcinomas (registered by the Tokai Ovarian Tumor Study Group from 1988 to 1999) were analyzed. Staging according to the International Federation of Gynecology and Obstetrics was set without considering the pathologic findings of the lymph nodes. Stage Ic was divided into Ic(b) and other Ic. RESULTS: Seventy-four patients were stage Ia, 2 were stage Ib, and 138 were stage Ic, consisting of 75 Ic(b) and 63 other Ic patients. The ratios of stage Ic to Ia and stage Ic(b) to Ic were highest in clear-cell adenocarcinoma among histologies analyzed. There were significant differences in disease-free survival curves between each group. In clear cell adenocarcinoma, there was a significant difference in disease- free survival curves between stage Ic(b) and other Ic (p = 0.0373), while this tendency was also observed in other histologies except for mucinous carcinoma. Multivariate analysis demonstrated that substage was a significant prognostic factor of both disease-free and overall survival. CONCLUSIONS: Stage Ic(b) patients showed poorer survival than stage Ia patients but better than survival in other Ic. Thus, cautious treatment of ovarian tumor during surgery is quite important to avoid rupture.

Adenocarcinoma, Clear Cell↗